Inherited Kidney Disorder Traced To Arrested Development Of Membranes

In individuals with an inherited kidney disorder known as Alport syndrome, a
membrane crucial to the kidney's function steadily degrades, splitting and
thinning until the vital organ fails. Now, researchers at the University of
Pennsylvania Medical Center report that arrested development in the kidney may
lie at the center of the deadly disease. The new findings are described in the
May 15 issue of the Journal of Clinical Investigation, which features an image
from the study on its cover.

The average human kidney faces daunting duty, filtering more than 70
liters of fluid each day through internal structures called glomerular tufts.
That filtering raises the local concentration of protease enzymes that can
slowly digest a critical component of the tufts -- the glomerular basement
membrane -- requiring that the membrane be highly resistant to the action of
these enzymes. In most people, the membrane is tough enough to stand up to these
conditions -- but not so in people with Alport syndrome, in whom the integrity
of membrane is gradually lost.

The scientists discovered that, in these people, a genetic mutation
known to be associated with the disease prevents a vital transformation process
from occuring in two foundational collagen proteins. In healthy individuals, the
two collagen proteins that form the fetal glomerular basement membranes switch
during normal development to become three different -- and much stronger --
collagens that are then used to build adult kidney membranes. In people with
Alport syndrome, however, this developmental transformation cannot occur. And,
over time, protease enzymes break down the two early-stage collagens left behind
in the disrupted process, thereby destroying the critical membrane.

"It's as though these people inherited a bad set of tires," explains
Eric G. Neilson, MD, C. Mahlon Kline Professor of Medicine and senior author on
the study. "The collagen proteins in their kidney membranes wear out sooner than
in normal people."

The rugged conditions within the kidney are probably the reason for the
switch-over between sets of collagens during development, according to the
investigators.

"The environment in which filtration occurs in the kidney is one in
which there are many protease enzymes present," Neilson says. "It's our
hypothesis that evolution provided several new collagen proteins to protect the
kidney from wearing out too quickly."

Alport syndrome affects about 1 in 10,000 children born in the United
States, although its frequency in some regions is higher. In Utah, for example,
the rate climbs to 1 in 5,000 births.

The five proteins analyzed in the study, all members of a group known as
Type IV collagens, are referred to as alpha-1, -2, -3, -4, and -5 collagens.
Alpha-1 and -2 collagens are abundant in many parts of the body in addition to
the fetal kidney, while the more specialized alpha-3, -4, and -5 collagens that
appear in the glomerular filtering unit of the adult kidney are less common.

The mutation known to be responsible for about 80 percent of Alport
syndrome cases disables production of the alpha-5 collagen; the affected gene,
COL4-alpha-5, is located on the X chromosome, so that it affects many more males
than females and is much more severe in males. In addition to its appearance in
the kidney, alpha-5 is also present in the ear, the eye, and the skin, and
individuals with the mutant gene are often deaf.

Interestingly, even though the genetic flaw affects only one of the
three collagens involved in construction of the glomerular basement membrane of
the adult kidney, all three are absent in the kidney membranes of people with
Alport syndrome. Although the reason for this is not known, Neilson notes that
alpha-3, -4, and -5 collagen chains are heavily cross-linked in the normal
membrane, which is one of the reasons for the membrane's strength and ability to
resist enzyme digestion. The absence of all three when only one is genetically
flawed might be the result of a related transcriptional or self-assembly
problem, Neilson suggests.

"These chains probably assemble in a coordinated way," Neilson says. "It
may be that certain chains need to pair in certain ways, so that if they don't
have the appropriate partner, they never get used."

The lead author on the paper is Penn research associate and instructor
Raghuram Kalluri, PhD. Coauthors on the study are Charles F. Shield III, MD, at
St. Francis Regional Medical Center, Wichita, Kansas; and Parvin Todd, PhD, and
Billy G. Hudson, PhD, at the University of Kansas Medical Center, Kansas City.
The work was supported by a series of grants from the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of
Health (NIH).

The University of Pennsylvania Medical Center's sponsored research ranks fifth
in the United States, based on grant support from the National Institutes of
Health, the primary funder of biomedical research in the nation -- $149 million
in federal fiscal year 1996. In addition, for the second consecutive year, the
institution posted the highest growth rate in its research activity -- 9.1
percent -- of the top ten U.S. academic medical centers during the same period.

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